Persons who have exceptionally high risk of cancer are studied to find explanations for their susceptibility. These unusual individuals are identified through referral by practitioners and by our own clinical observations at the bedside. With informed consent, epidemiologic inquiries are made to identify predisposing host and environmental factors, and to quantify the risk of cancer development. Concurrent laboratory studies are made to clarify biologic mechanisms of cancer susceptibility. Results show that carriers of cancer genes develop cancer at high rates in specific tissues, including multiple primary cancers in childhood. Work is in progress to map several tumor suppressor genes, including genes for renal carcinoma, familial Wilms' tumor, and the dominantly inherited syndrome of breast cancer, sarcomas and other childhood neoplasms (Li-Fraumeni family cancer syndrome). In another study, nearly 1000 patients are under surveil- lance for the occurrence of second cancers through the Registry of Survivors of Childhood Cancer in Boston. An additional series of nearly 2000 survivors of childhood retinoblastoma in New York and Boston are being examined for the role of inherited susceptibility and ionizing radiation therapy in the development of second cancers.